The oral bioavailability of certain drugs can be improved by conversion to prodrugs. Certain prodrugs are derivatives of the parent drug in which a functional group is “masked” by a promoiety. Following administration to a patient the prodrug is metabolized to release the parent drug. The 1-(acyloxy)-alkyl group is an example of a promoiety that has been used to functionalize amine-containing drugs such as pregabalin and baclofen.
Pregabalin ((3S)-(aminomethyl)-5-methyl-hexanoic acid) is an FDA approved drug that is marketed for the treatment of, for example, post herpetic neuralgia, peripheral diabetic neuropathy, fibromyalgia, and epilepsy. Pregabalin is not absorbed from the lower gastrointestinal tract and exhibits a short half life in vivo, and therefore frequent dosing is required to maintain therapeutic levels in the body when orally administered. (3S)-{[1-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid, (3S)-{[1-isobutanoyloxyisobutoxy]carbonylaminomethyl}-5-methyl-hexanoic acid, and (3S)-{[1-benzoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid are examples of 1-(acyloxy)-alkyl carbamate prodrugs of pregabalin, which exhibit high bioavailability as pregabalin when dosed either orally or directly into the colon of a mammal (Gallop et al., U.S. Pat. Nos. 6,972,341 and 7,186,855; and Yao and Gallop, U.S. Provisional Application Nos. 61/023,808 filed Jan. 25, 2008 and 61/023,813 filed Jan. 25, 2008, each of which is incorporated by reference in its entirety).
The 1-(acyloxy)-alkyl promoiety has also been used to provide prodrugs of baclofen, (±)-4-amino-3-(4-chlorophenyl)butanoic acid. Gallop et al., U.S. Pat. No. 7,109,239 and U.S. Pat. No. 7,300,956 (each of which is incorporated by reference in its entirety) disclose 1-(acyloxy)-alkyl carbamate prodrugs of R-baclofen such as (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl)butanoic acid. Baclofen is an analog of gamma-aminobutyric acid (GABA) that selectively activates GABAB receptors, resulting in neuronal hyperpolarization. Baclofen is an FDA approved drug that is marketed for the treatment of spasticity and muscle relaxation. More recent studies have indicated that the R-isomer of baclofen is effective for treating gastroesophageal reflux disease (GERD). Baclofen and R-baclofen, like pregabalin, have poor colonic absorption and a short half life in vivo, and when orally administered frequent dosing is required to maintain therapeutic levels in the body.
The (acyloxy)alkylcarbamate functionality has been widely used to prepare prodrugs for therapeutics containing amine groups (Gogate et al., International Journal of Pharmaceutics 1987, 40, 235-248; Alexander et al., J. Med. Chem. 1988, 31, 318-322; Sun et al., Bioorganic & Medicinal Chemistry Letters 2001, 11, 1875-1879; Alexander et al., J. Med. Chem. 1991, 34, 78-81; and Gallop et al., U.S. Pat. No. 6,972,341). Methods of synthesizing 1-(acyloxy)-alkyl carbamate prodrugs are disclosed in Gallop et al., U.S. Pat. Nos. 6,818,787, 6,927,036, 6,972,341, 7,186,855, 7,026,351, 7,109,239, and 7,227,028; Raillard et al., U.S. Pat. No. 7,232,924; Gallop and Bhat, WO 2005/010011; Raillard et al., U.S. Provisional Application No. 61/087,056 filed Aug. 7, 2008 and 61/087,038 filed Aug. 7, 2008, each of which is incorporated by reference in its entirety); and in Alexander, U.S. Pat. Nos. 4,760,057, 4,916,230, and 5,684,018. One method, as outlined in FIG. 1, involves an acyloxyalkylthiocarbonate intermediate (Sun et al., Bioorganic & Medicinal Chemistry Letters 2001, 11, 1875-1879; and Gallop et al., U.S. Pat. Nos. 7,026,351 and 7,227,028).
A deficiency common to such methods for synthesizing acyloxyalkyl derivatives is that, except when the R2 substituent is hydrogen, the prodrugs are generated as racemates or diastereomeric mixtures. The presence of an additional chiral center in the promoiety may lead to differences in the physical properties and in the pharmacokinetics of the prodrug. Complexities associated with the introduction of an uncontrolled stereocenter in acyloxyalkyl promoieties have led others to focus prodrug design efforts around the achiral acyloxymethyl moiety (R2 is hydrogen). Further, many (acyloxy)alkylcarbamate prodrugs generate formaldehyde as a toxic metabolite during hydrolysis in vivo. In comparison with acetaldehyde, formaldehyde shows greater acute mammalian toxicity and mutagenicity, and its oxidative metabolite formate is associated with specific ocular toxicity in humans. Furthermore, because the thiocarbonates do not have acidic or basic functional groups, they are not readily resolved by classical chemical methods.
Thus, improved methods of synthesizing enantiomerically enriched acyloxyalkyl thiocarbonates are desirable.